The present invention relates to an external agent for the skin and a novel compound that is applicable thereto. More particularly, the present invention relates to an external agent for the skin that contains a compound having an inhibitory activity against melanine synthesis, that is excellent in the prevention and amelioration of skin pigmentation and that is suitable for cosmetics for whitening, and a novel compound having an inhibitory activity against melanine synthesis used preferably thereto.
Skin pigmentation that causes blotches, freckles, and blackening of the skin after sunburnt is attributed to considerable sthenia of melanine synthesis, which is in turn due to activation of melanocytes in the skin. This is one of problems concerning the skin of middle- to high-aged persons. Accordingly, in order to prevent or ameliorate such a trouble on the skin pigmentation, there have been known external agents far the skin that contain ascorbic acids, aqueous hydrogen peroxide, glutathione, colloidal sulfur, hydroquinone, cathecol or the like.
However, for the prevention and amelioration of skin pigmentation as described above, ascorbic acids tend to be oxidized and thus are unstable and causes discoloration in systems that contain much moisture, such as water-contained cosmetics. Also, aqueous hydrogen peroxide has the problems of stability during storage and safety while glutathione and colloidal sulfur give strong undesirable odors so that their use in products is restricted. Further, those additives such as hydroquinone and cathecol may have the problems of safety, such as skin irritation and allergy. Therefore, there has been currently obtained no external agent for the skin which is satisfactory in the prevention and amelioration of skin pigmentation. That is, there has been a need for a novel external agent for the skin that is safe and has an excellent whitening activity.
On the other hand, among compounds represented by formula (1) used for the external agent for the skin of the present invention, those in which R is a hydrogen atom are known compounds which are described in U. S. Pat. Nos. 2,418,458/1947 and 2,418,459/1947, and the like. Further, it is also known that inulavosin among these compounds has fish toxin activity and antibacterial activity, for example, that for Staphylococcus aureus, Pseudomonas aeruginosa, and the like (Heterocycles, Vol. 41, No. 9, 1923-1926 (1995)). However, it has not been known that the compounds represented by formula (I) inclusive of the above compounds have an inhibitory activity against melanine synthesis in skin. Further, it has not been reported that the compounds represented by formula (I) are used for an external agent for the skin to prevent and ameliorate of skin pigmentation.
Under the circumstances, the present invention has been made and an object of the present invention is to provide an external agent for the skin that not only exhibits excellent effects of prevention and amelioration of skin pigmentation but also has no fear of giving adverse influences to the skin and can be used safely.
The term xe2x80x9cexternal agent for the skinxe2x80x9d as used herein refers to a composition of any type of formula that can be administered to the skin and be pooled there continuously, used in a broad concept including cosmetics, quasi-drugs, external medicines for the skin and the like.
As a result of intensive investigation with a view to achieve the above-described object, the present inventors have discovered that compounds represented by formula (I), below have strong inhibitory activity against the melanine synthesis by live melanocytes and further that they exhibit excellent effects of prevention and amelioration of skin pigmentation when they are contained in a basic formulation of external agents for the skin. Also, the present inventors have newly produced the compounds having the above-described activity. Based on these, the present invention has been completed.
That is, the present invention relates to an external agent for the skin comprising one or more compound(s) selected from compounds represented by formula (I) below: 
(wherein R1, R2, R3, R4, and R5, independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and R represents a hydrogen atom, an acyl group, or a sugar residue).
In a preferred embodiment of the external agent for the skin of the present invention, content of one or more compound(s) selected from the compounds represented by formula (I) ranges in an amount from 0.0045 to 10% by weight based on the total weight of the external agent. The external agent for the skin of the present invention is used advantageously as an external agent for the skin for whitening the skin.
Also, the present invention relates to a compound represented by formula (III) below: 
(wherein R1, R2, R3, R4, and R5, independently represent a hydrogen atom or an alkyl group having to 4 carbon atoms; and R7, represents an acyl group or a sugar residue).
Hereafter, the present invention will be described in detail.
(1) Compound represented by formula (I) that is an essential component of the external agent for the skin of the present invention
The external agent for the skin of the present invention contains one or more compounds represented by formula (I) above as an essential component. In formula (I), R1, R2, R3, R4, and R5, independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The alkyl group having 1 to 4 carbon atoms may be either of a straight or branched chain and specifically includes a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, or a tert-butyl group, and the like. Among these, a methyl group is particularly preferred.
In formula (I), R represents a hydrogen atom of a hydroxyl group or a substituent of the hydrogen atom of a hydroxyl group, more specifically an acyl group or a sugar residue. Specifically, the acyl group includes an acyl group represented by R6xe2x80x94COxe2x80x94, wherein R6 represents an alkyl group having 1 to 17 carbon atoms or an alkenyl group having one or two double bonds and 3 to 17 carbon atoms, and mare specifically an acetyl group, a pentanoyl group, an isooctanoyl group, a stearoyl group, an isostearoyl group, an oleoyl group, an octadecadienoyl and the like. The above-described sugar residue is not limited particularly and includes any sugar residue having a glucoside linkage terminal, wherein the sugar is a monosaccharide or disachharide that can be connected through a glucoside linkage. Specific examples thereof include a glucose residue, a xylose residue, a fructose residue, an arabinose residue, a rhamnose residue, a galactose residue, a sucrose residue, a maltose residue, and the like.
Further, among the compounds represented by formula (I) above, those compounds preferably used for external agent for the skin of the present invention include compounds represented by formula (II) below: 
(wherein R represents a hydrogen atom, an acyl group represented by R6xe2x80x94COxe2x80x94 or a sugar residue; in which R6 represents an alkyl group having 1 to 17 carbon atoms or an alkenyl group having one or two double bonds and 3 to 17 carbon atoms).
The compounds represented by formula (II) above are compounds represented by formula (I) in which R1, R2, R3, R4, and R5 are each a methyl group. Further, as the acyl group or sugar residue represented by R in formula (II), there may be cited the same acyl group or sugar residue in the compounds represented by formula (I) above.
Among the compounds represented by formula (I) above, those in which R is a hydrogen atom are known compounds. Methods for their synthesis are described in U. S. Pat. Nos. 2,418,458/1947 and 2,418,459/1947. The above-described compounds produced by such methods can be used in the present invention.
Further, among the compounds represented by formula (II) that are used advantageously in the present invention, the compound in which R is a hydrogen atom is known as inulavosin. It is also known that the compound has fish toxin activity and antibacterial activity, for example that for Staphylococcus aureus, Pseudomonas aeruqinosa, and the like (Heterocycles, Vol. 41, No. 9, 1923-1926 (1995)). Also, inulavosin can be produced by the method as described above.
However, it has not been known that the compounds represented by formula (I) above in which R is a hydrogen atom, inclusive of inulavosin, have an inhibitory activity against melanine synthesis in skin. Further, it has not been known that direct application of the compounds to the skin based on the above-described activity gives rise to so-called whitening effects such as excellent prevention and amelioration of skin pigmentation that would lead to blotches, freckles, blackening of skin after sunburnt or chromatosis such as melanosis. It is believed that the present inventors have found this for the first time.
Further, among the compounds represented by formula-(I), the compounds represented by formula (III) below are novel compounds that are not described in the literature. The compounds represented by formula (III) correspond to the acylated compounds or glycosides of the compounds represented by formula (I) above in which R is a hydrogen atom. 
(wherein R1, R2, R3, R4, and R5, independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and R7 represents an acyl group or a sugar residue).
In formula (III) above, examples of R1, R2, R3, R4, and R5, may be cited the same as those for R1, R2, R3, R4, and R5, in formula (I) above. Further, as the aryl group or sugar residue represented by R7, there may be cited the same acyl group or sugar residue in the compounds represented by formula (I) above.
Further, among the novel compounds represented by formula (III) above, those compounds represented by formula (IV) below are compounds that can be used advantageously in the external agent for the skin of the present invention. The compounds represented by formula (IV) correspond to the acylated compounds or glycosides of the above inulavosin. 
(wherein R7, represents an acyl group represented by R8xe2x80x94COxe2x80x94 or a sugar residue; in which R8 represents an alkyl group having 1 to 17 carbon atoms or an alkenyl group having one or two double bonds and 3 to 17 carbon atoms).
The compounds represented by formula (IV) above are compounds represented by formula (III) in which R1, R2, R3, R4, and R5, are each a methyl group. Further, as the acyl group or sugar residue represented by R7 in formula (IV), there may be cited the same acyl group or sugar residue in the compounds represented by formula (III) above.
Further, of these novel compounds, particularly preferred compounds to be applied to the external agent for the skin of the present invention include acetylinulavosin and glycosides of inulavosin.
These novel compounds can be produced by a conventional method using a known compound represented by formula (I) in which R is a hydrogen atom such as inulavosin, for example, by condensation reaction with an acylating agent such as aryl chloride when the targeted compound is an acylated compound, or with a halide of a sugar using silver nitrate or silver oxide as a catalyst when the targeted compound is a glycoside.
(2) External agent for the skin of the present invention
The external agent for the skin of the present invention is characterized by containing one or more compound(s) selected from the compounds represented by formula (I) above. Among the compounds represented by formula (I), preferred for the external agent for the skin of the present invention are inulavosin, acylinuolavosin, and inulavosin glycosides represented by formula (II) above. Of these, inulavosin, acetylinulavosin and inulavosin glucosides are particularly preferred.
In the present invention, addition of one or more compound(s) represented by formula (I) in a basic formulation of external agent for the skin allows exhibition of excellent whitening effect based on the inhibitory activity against melanine synthesis. The content of the above-described compound or compounds ranges preferably in an amount from 0.0005 to 10% by weight based on the total weight of the external agent for the skin. Of course, as stated above, the external agent for the skin of the present invention may include the compounds represented by formula (I) singly or in combination of two or more of them. When two or more of compounds are used in combination, a preferred range of the above-described content may be considered a range of the sum of the contents of the compounds represented by formula (I).
That is, when the external agent for the skin is used for preventing skin pigmentation that would cause blotches, freckles, blackening of skin after sunburnt or chromatosis such as melanosis, its content is desirably 0.0005% or more by weight in point of effect. Further, when the external agent far the skin is used for ameliorating skin pigmentation, its content is preferably 0.1% or more by weight, and more preferably 1% or more by weight in point of effect. As will be apparent from the experimental results described hereinbelow, when the content of the above-described compound is less than 0.0005% by weight, the tendency is observed that the inhibitory activity against melanine synthesis is decreased considerably while in spite of use of the amount of above 10% by weight, the effect reaches a plateau. Therefore, it is desirable that the external agent for the skin of the present invention contains the compound(s) in the above-described range.
Also, the external agent for the skin of the present invention is desirably one that is used in the form in which it is pooled on the skin continuously in view of the characteristics of the compound or compounds activity represented by general formula (I) that the external agent for the skin of the present invention contains as an essential component. In this respect, it can be said that most external agents for the skin conventionally used take application forms desirable for the external agent for the skin of the present invention. Although a washing agent is one embodiment of the external agent for the skin of the present invention, it cannot be said to be a preferred embodiment of the external agent for the skin of the present invention since its application form is temporary in nature, on the other hand, a pack material or the like has a shielding effect, though its contact time with skin is short, so that it is a preferred embodiment of the external agent for the skin of the present invention.
The external agent for the skin of the present invention can be obtained by blending one or more compounds selected from the compounds represented by formula (I) above in a basic formulation far external agents for the skin conventionally used for external agents for the skin, such as external medicines for the skin, cosmetics, and the like by a conventional method and can be produced in the same manner as the conventional external agents for the skin except that one or more compounds selected from the compounds represented by formula (I) above is or are blended therein.
As components of the basic formulation for the above-described external agents for the skin, there can be cited, for example, a moisture component, an oil component, a power component, a surfactant, a tackifier, a colorant, a fragrant, an anti-oxidant, a pH adjusting agent, a chelating agent, a preservative and the like. In addition to the compounds represented by formula (I), the external agent for the skin of the present invention may optionally contain one or more medical components such as a humectant, an ultraviolet shielding agent, and an anti-inflammatory agent. Further, in addition to the compounds represented by formula (I), the external agent for the skin of the present invention may optionally contain one or more whitening components such as a whitening agent, for example, pantetheine-S-sulfonic acid, isoferulic acid, magnesium phosphate ascorbic acid salt, arbutin, kojic acid, rinolic acid, methyl tinplate, and the like.
Further, the application form of the external agent for the skin of the present invention may be of any type conventionally used for this type of external agent for the skin and includes, for example, ointment, cream, emulsion, lotion, pack and the like application forms.
Applications of the external agent for the skin of the present invention include cosmetics, quasi-drugs, external medicine for the skin and the like. Further, the external agents for the skin can be used advantageously for whitening.